Amphiphilic block copolymers include a hydrophilic block and a hydrophobic block, and in an aqueous solution, the hydrophobic block forms a core and the hydrophilic block forms a shell, thereby forming micelles each having a core-shell structure and a tens to hundreds nanometer-size.
Conventional amphiphilic block copolymers for preparing polymer micelles are categorized into a polymer that does not include a functional group and a polymer that includes a plurality of functional groups. The polymer that does not include a functional group may not sufficiently interact with hydrophobic drugs, and also has limitations on the development and application of a drug delivery system, and the polymer that includes a plurality of functional groups dissolves in water, and thus, may insufficiently encapsulate drugs (Korean Patent Publication No. 2004-0021760).
As a method of synthesizing a B A B-type tri-block copolymer by using AB-type initial polymer, a method of preparing a BA-AB type block copolymer by using a crosslinker is generally known, and examples of the crosslinker are hexamethylene diisocyanate and adipoyl chloride.
A B A B-type block copolymer prepared by using hexamethylene diisocyanate as a crosslinker is synthesized by urethane binding of hydrophobic A block (Jeong et al., nature, 388, 860-862, 1997). When adipoyl chloride is used as a crosslinker, a hydrochloric acid is formed as a by-product, and due to the hydrochloric acid, the hydrophobic A block may easily decompose (Feng Li et al., Langmuir, 23, 2778-2783, 2007).
In particular, a crosslinker for use in the preparation of a BA-AB type copolymer is reported as being toxic in vivo, and during reaction, AB-type initial polymer may decompose. Also, even the formed BA-AB type copolymer may be difficult to have a functional group at both ends of a hydrophilic B group. Accordingly, the copolymer is used as a drug delivery system having only a drug delivery purpose.
In response, the inventors of the present application, unlike the production of a BA-AB-type copolymer using hexamethylene diisocyanate and adipoyl chloride as a crosslinker, combined an AB-type initial polymer and an equivalent or different molecular weight of polyethylene glycol (B) to produce a B A B-type tri-block copolymer without the use of a crosslinker. By doing so, existing problems stemming from the use of a crosslinker are overcome, a block is formed to easily control the molecular weight of a polymer, and a symmetric or asymmetric copolymer having a varying molecular weight can be synthesized. Also, due to the introduction of polyethylene glycol, stability of the amphipilic polymer increases, and since a functional group at the terminal of the polyethylene glycol is changed to introduce functionality, targeting is possible and poor-soluble drugs may be encapsulated by a hydrophobic block of micelles formed by self-assembling such copolymers, leading to use of an intelligent drug delivery system.